{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:26:15Z","timestamp":1783542375029,"version":"3.55.0"},"reference-count":13,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the\n              <jats:italic>KCND3<\/jats:italic>\n              -encoded Kv4.3 pore-forming \u03b1-subunit.\n              <jats:italic>KCND3<\/jats:italic>\n              gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome and early repolarization syndrome, as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. Acacetin may be a novel therapeutic for\n              <jats:italic>KCND3<\/jats:italic>\n              -mediated J wave syndrome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              KCND3-V392I was identified in an 18-year-old male with J wave syndrome\/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia\/ventricular fibrillation and atrial fibrillation\/atrial flutter. Pathogenic\n              <jats:italic>KCND3<\/jats:italic>\n              mutation was engineered by site-directed mutagenesis and co-expressed with wild-type KChIP2 in TSA201 cells. Gene-edited\/variant-corrected isogenic control and patient-specific pluripotent stem cell\u2013derived cardiomyocytes (iPSC-CMs) from the p. Val392Ile-KCND3-positive patient were generated. I\n              <jats:sub>to<\/jats:sub>\n              currents and action potentials were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak I\n              <jats:sub>to<\/jats:sub>\n              current density by 92.2% (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05 versus KCND3-WT). KCND3 expression was significantly increased in KCND3-V392I-derived iPSC-CMs (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05 versus isogenic control). While KCND3-WT revealed an IC50 of 7.2\u00b11.0 \u00b5mol\/L for acacetin effect, 30 \u00b5mol\/L acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96.2% (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05 versus before Acacetin). Ito was also increased by 60.9% in Kv4.3-V392I iPSC-CM (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05 versus isogenic control iPSC-CM). Ten micromoles per liter acacetin, a concentration approaching its IC50 value, inhibited Ito by \u224850% in patient-derived iPSC-CMs and reduced the accentuated action potential notch displayed in KCND3-V392I-derived iPSC-CMs.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              This preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I\n              <jats:sub>to<\/jats:sub>\n              and abolishing the accentuated action potential notch in patient-derived iPSC-CMs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.120.003238","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T09:18:19Z","timestamp":1657617499000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Acacetin, a Potent Transient Outward Current Blocker, May Be a Novel Therapeutic for\n            <i>KCND3<\/i>\n            -Encoded Kv4.3 Gain-of-Function-Associated J-Wave Syndromes"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0619-7070","authenticated-orcid":true,"given":"Dan","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8680-2906","authenticated-orcid":true,"given":"Samantha K.","family":"Hamrick","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4554-2244","authenticated-orcid":true,"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.S. John","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2704-3807","authenticated-orcid":true,"given":"Hector","family":"Barajas-Martinez","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (H.B.-M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0994-8434","authenticated-orcid":true,"given":"Dan","family":"Hu","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (H.B.-M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-0265","authenticated-orcid":true,"given":"John R.","family":"Giudicessi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7349-1582","authenticated-orcid":true,"given":"Charles","family":"Antzelevitch","sequence":"additional","affiliation":[{"name":"Lankenau Institute for Medical Research, Wynnewood, PA (H.B.-M., C.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8011-3333","authenticated-orcid":true,"given":"Michael J.","family":"Ackerman","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Cardiovascular Medicine\/Division of Heart Rhythm Services (Windland Smith Rice Genetic Heart Rhythm Clinic) (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."},{"name":"Department of Pediatric and Adolescent Medicine\/Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN (D.Y., W.Z., S.K.H., D.J.T., C.S.J.K., J.R.G., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.02.021"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.cj-12-0284"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22058"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.12.006"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euw235"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2018.02.009"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000143159.30585.90"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.100.15.1660"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.4161\/chan.3.4.9254"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.769554"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0057864"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1159\/000366343"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0242747"}],"container-title":["Circulation: Genomic and Precision Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGEN.120.003238","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:43:28Z","timestamp":1715564608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGEN.120.003238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":13,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1161\/CIRCGEN.120.003238"],"URL":"https:\/\/doi.org\/10.1161\/circgen.120.003238","relation":{},"ISSN":["2574-8300"],"issn-type":[{"value":"2574-8300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10]]},"assertion":[{"value":"2020-10-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}